Squamous cell carcinoma (SCC) is a significant public health issue worldwide. In the United States, it afflicts more than 200,000 people each year. SCC arises in the skin, upper aerodigestive tract, lung and cervix, accounting for 25 percent of all skin cancers, approximately one-third of all cases of bronchogenic carcinomas, approximately 95 percent of all esophageal cancers, 80-90 percent of all cervical cancers and at least 90 percent of the head and neck cancers. Despite optimal treatment with surgery, irradiation, and chemotherapy, disease recurrence and progression remains a challenging issue. There is a compelling need for innovative therapeutic interventions on those patients at high risk for recurrence and death. Development of SCC involves mutations of genes that are involved in cell growth control or tumor suppression. Our recent studies indicate that Id1, a member of the inhibitor of differentiation (Id)family which is involved in cell proliferation and angiogenesis, is mutated or up-regulated in head and neck SCC patients. Our preliminary studies indicated that the Id1 mutant is involved in cell proliferation of SCC and up-regulation of pro-angiogenic cytokines: vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). It suggests that the Id1 mutant plays an important role in the carcinogenesis and angiogenesis of SCC. In this application, we will focus on the molecular mechanisms of the Id1 mutant in the progression and malignancy of SCC. Firstly, we will study the incidence of the Id1 mutant in SCC patients by real-time PCR and immunohistochemistry. Secondly, we will investigate the molecular mechanism by which the Id1 mutant induces the proliferation of SCC by cellular and molecular biologic techniques. Finally, we will determine the molecular mechanisms by which the Id1 mutant up-regulates the expression of angiogenic cytokines (VEGF and IL-8) by luciferase reporter assays. The study not only improves our understanding of the molecular mechanisms on the carcinogenesis and angiogenesis of SCC but also provides a foundation for innovative treatment against SCC in the future.